Our goal is to identify and characterize new genes, pathways and molecular mechanisms that contribute to elevated IOP and glaucoma. This is a critical step for rationally improving the care of patients. Elevated intraocular pressure (IOP) isa major risk factor for glaucoma. The mechanisms underlying IOP elevation and glaucoma are largely unidentified. We study the genetics of glaucoma using both the human and mouse. Using mice to discover glaucoma pathways is an important approach, as mice are experimentally tractable, and it remains difficult to identify many glaucoma genes in patient populations. (Aim 1) We will use the power of mouse genetics to identify novel genes and mechanisms that induce IOP elevation in new glaucoma-relevant mutants that we have discovered and started to study. We will characterize the genetic pathways involved and carry out more detailed investigations into the molecular pathogenesis. We will collaborate to assess the human orthologs of the identified genes in human patients. (Aim 2) The limited availability of useful mutants remains a major factor hindering glaucoma gene discovery using mice. Thus, we will conduct a phenotype driven mutagenesis screen to identify novel genes and molecular mechanisms involved in IOP elevation and glaucoma. We propose a sensitized ENU screen for glaucoma mutations. We will sensitize the screen in various ways including a mutation in the mouse ortholog of a human gene that predisposes people to high IOP and glaucoma, a predisposition that we have repeated in mice. To hasten the discovery of glaucoma-relevant genes and mechanisms, we will complement genetics with state-of-the-art sequencing and genomic approaches. Continuing to use the power of a phenotype-driven mutagenesis screen, in parallel with our proven experience in determining disease mechanisms and in examining ocular phenotypes, will enable us to identify and characterize new genes and molecular processes that contribute to elevated IOP and glaucoma. The new mutants will have great potential to transform our understanding of glaucoma.